Effects of various known and potential cyanide antagonists and a glutathione depletor on acute toxicity of cyanide in mice.
To compare the protective potencies of a large number of known and potential cyanide antagonists in one stock of mice, groups (N = 10) of male CF-1 Swiss-Webster mice were given a single maximal or near-maximal intraperitoneal injection of each substance. Ethyl maleate, a glutathione (GSH) depletor and potential enhancer of cyanide toxicity, was given to other groups. Thirty min later, the mice were given subcutaneous injections of graded doses of KCN. In untreated control mice, the 24-hr median lethal dose (LD50) of KCN was 11 mg/kg of body weight (potency ratio, PR = 1.0). In comparison, protective effects of traditional antagonists thiosulfate and nitrite produced PR values of 1.48 and 2.95, respectively. Tetrathionate, sulfate, dithionite, methionine, hydroxocobalamin, ascorbate, pyridoxal phosphate, alpha-ketoglutarate, alpha-ketobutyrate, GSH, GSH disulfide (GSSG) and selenite were similar in efficacy to thiosulfate (P less than 0.05; PR values 1.35-1.59). Cysteine, diethyldithiocarbamate (DEDC), and cobaltous chloride were more effective than thiosulfate (PR values 1.68, 1.69, and 1.85, respectively). Phentolamine and dicobalt EDTA were ineffective, whereas papaverine enhanced toxicity (PR 0.72). Agents with significant PR values (greater than or equal to 1.14) but which were less effective than thiosulfate included sulfite, dimercaptosuccinic acid, pyruvate, citrate, alpha-ketovalerate, naloxone, and corn oil. Ethyl maleate in corn oil markedly enhanced KCN lethality (PR 0.57 compared to corn oil alone), and caused prolonged illness in several mice. Vitamin E in corn oil had no effect. Dual mixtures of thiosulfate with other selected substances were also tested.(ABSTRACT TRUNCATED AT 250 WORDS)
Hatch
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Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens 30602.
Laflamme
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Jain
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D000818:Animals; D003486:Cyanides / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000037:antagonists & inhibitors*; D007928:Lethal Dose 50; D008706:Methemoglobin / Q000378:metabolism; D051379:Mice; D013056:Spectrophotometry, Ultraviolet; D013885:Thiosulfates / Q000494:pharmacology
D003486:Cyanides; D013885:Thiosulfates; D008706:Methemoglobin; D005978:Glutathione